The development of new treatments for neurodegenerative diseases is a major unmet medical need, with the numbers of affected individuals (already tens of millions worldwide) projected to dramatically increase with the aging population. Axonal dysfunction appears to be an early event in many of these disorders, thus it has become a prime focus for the development of new treatments for these conditions. AxD is a self-destructive process that is similar to, but distinct from, apoptosis. Most studies indicate that it is a caspase-independent process as manipulation of the mitochondrial apoptotic machinery or caspase inhibitors fail to block AxD. However, the recent identification of an APP/DR6/Casp6 axon degeneration pathway induced by trophic factor deprivation suggests a link between these two processes. Studies of the wlds mutant mouse led to the discovery that the NAD biosynthetic enzyme Nmnat1 can protect axons from a wide variety of insults, including mechanical trauma, loss of trophic support, and mitochondrial inhibition. Nmnat enzymatic activity is required for the axonal protective effects; however, its mechanism of action remains obscure. In this proposal, we outline experiments aimed at 1) identifying the signaling pathway(s) responsible for axonal surface APP (sAPP) shedding, caspase 6 (Casp6) cleavage, and axonal degeneration (AxD) induced by trophic factor deprivation using Ret knockin Tyr->Phe mutant mice; 2) understanding the mechanism by which Nmnat protects axons after trophic factor deprivation without altering cleaved Casp6 levels via monitoring cleavage of Casp6 targets; 3) investigating the idea that different Nmnat isoforms produce NAD for specific neuronal subcellular compartments important for axonal integrity or that they have additional functions besides NAD production, such as the synthesis of novel metabolites that are important mediators of axonal protection; and 4) testing the therapeutic efficacy of combined neurotrophic factor and axonal protectant treatment in animal models of Parkinson's disease. If the proposed combination therapy shows dramatically increased benefit over single agent therapy in the PD models, this could have a wide-ranging impact as it is likely to be applicable to other neurodegenerative diseases. Overall, we believe that understanding the convergence of growth factor signaling and the common Nmnat-sensitive pathway of axon self-destruction could foster new therapeutic strategies for a wide range of disease and injury conditions.